Loss of tolerance precedes triggering and lifelong persistence of pathogenic type I interferon autoantibodies

Sonja Fernbach, Nina K Mair, Irene A Abela, Kevin Groen, Roger Kuratli, Marie Lork, Christian W Thorball, Enos Bernasconi, Paraskevas Filippidis, Karoline Leuzinger, Julia Notter, Andri Rauch, Hans H Hirsch, Michael Huber, Huldrych F Günthard, Jacques Fellay, Roger D Kouyos, Benjamin G Hale, Swiss HIV Cohort Study

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12 Citationer (Scopus)

Abstract

Autoantibodies neutralizing type I interferons (IFN-Is) can underlie infection severity. Here, we trace the development of these autoantibodies at high-resolution using longitudinal samples from 1,876 well-treated individuals living with HIV over a 35-year period. Similar to general populations, ∼1.9% of individuals acquired anti-IFN-I autoantibodies as they aged (median onset ∼63 years). Once detected, anti-IFN-I autoantibodies persisted lifelong, and titers increased over decades. Individuals developed distinct neutralizing and non-neutralizing autoantibody repertoires at discrete times that selectively targeted combinations of IFNα, IFNβ, and IFNω. Emergence of neutralizing anti-IFNα autoantibodies correlated with reduced baseline IFN-stimulated gene levels and was associated with subsequent susceptibility to severe COVID-19 several years later. Retrospective measurements revealed enrichment of pre-existing autoreactivity against other autoantigens in individuals who later developed anti-IFN-I autoantibodies, and there was evidence for prior viral infections or increased IFN at the time of anti-IFN-I autoantibody triggering. These analyses suggest that age-related loss of self-tolerance prior to IFN-I immune-triggering poses a risk of developing lifelong functional IFN-I deficiency.

OriginalsprogEngelsk
Artikelnummere20240365
TidsskriftThe Journal of Experimental Medicine
Vol/bind221
Udgave nummer9
Antal sider21
ISSN0022-1007
DOI
StatusUdgivet - 2 sep. 2024
Udgivet eksterntJa

Bibliografisk note

© 2024 Fernbach et al.

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